BRCA-deficient metastatic prostate cancer has an adverse prognosis and distinct genomic phenotype.
BRCA-deficient metastatic prostate cancer has an adverse prognosis and distinct genomic phenotype.
复制标题
DOI：
10.1016/j.ebiom.2023.104738
复制
发表时间：
2023-09
期刊：
影响因子：
11.1
通讯作者：
Azad, Arun A.
中科院分区：
文献类型：
--
作者：
Fettke, Heidi;Dai, Chao;Kwan, Edmond M.;Zheng, Tiantian;Du, Pan;Ng, Nicole;Bukczynska, Patricia;Docanto, Maria;Kostos, Louise;Foroughi, Siavash;Brown, Stephen;Graham, Lisa-Jane K.;Mahon, Kate;Horvath, Lisa G.;Jia, Shidong;Kohli, Manish;Azad, Arun A.
DNA损伤反应（DDR）基因的基因组改变在转移性去势抵抗性前列腺癌（mCRPC）中很常见。了解这些基因组事件如何影响预后和/或治疗反应对于优化临床结果至关重要。对来自375名mCRPC男性的407份血浆样本进行靶向测序。使用CLIA认证的PredicineCARE™无细胞DNA（cfDNA）检测，评估了152个关键基因（包括27个DDR相关基因）的致病性改变，以及BRCA 2中双等位基因丢失的存在和机制。在34.5%（129/375）的患者中存在至少一种DDR改变（包括单等位基因改变）。最常见的DDR基因是BRCA 2（19%），ATM（13%），FANCA（5%），CHEK 2（5%）和BRCA 1（3%）。BRCA改变的患者，尤其是BRCA 2改变的患者，无进展生存期（PFS）显著更差。（风险比（HR）3.3 [95% CI 1.9-6.0];考克斯回归p < 0.001），总生存期（HR 2.2 [95% CI 1.1-4.5];考克斯回归p = 0.02）和雄激素受体（AR）通路抑制剂的PSA缓解率（32% vs 60%，卡方检验p = 0.02）。BRCA缺陷型肿瘤也富含多个基因内的改变，包括AR和PI 3 K通路。BRCA 2改变的合子性对临床结局没有明显影响，单等位基因丢失与双等位基因丢失的PFS相似（中位3.9个月vs 3.4个月vs拷贝中性9.8个月）。这些数据强调了BRCA基因，特别是BRCA 2，是mCRPC的关键预后生物标志物。BRCA 2作为不良结局标志物的临床效用可能至少在cfDNA测定中与检测到的接合性状态无关。在来自BRCA缺陷型mCRPC的cfDNA中富集可操作的基因组改变可能支持未来临床试验中的合理共靶向策略。一些资金来源支持这项研究。完整的清单见致谢。没有收到任何资金。在研究进行期间。
Genomic alterations in DNA damage response (DDR) genes are common in metastatic castration-resistant prostate cancer (mCRPC). Understanding how these genomic events impact prognosis and/or treatment response is vital for optimising clinical outcomes. Targeted sequencing was performed on 407 plasma samples from 375 men with mCRPC. Using the CLIA-certified PredicineCARE™ cell-free DNA (cfDNA) assay, pathogenic alterations in 152 key genes (including 27 DDR-related genes) were assessed, as was the presence and mechanisms of biallelic loss in BRCA2. At least one DDR alteration was present in 34.5% (129/375) of patients (including monoallelic alterations). The most frequently altered DDR genes were BRCA2 (19%), ATM (13%), FANCA (5%), CHEK2 (5%) and BRCA1 (3%). Patients with BRCA alterations, especially BRCA2, had significantly worse progression-free survival (PFS) (Hazard ratio (HR) 3.3 [95% CI 1.9–6.0]; Cox regression p < 0.001), overall survival (HR 2.2 [95% CI 1.1–4.5]; Cox regression p = 0.02) and PSA response rates to androgen receptor (AR) pathway inhibitors (32% vs 60%, chi-square p = 0.02). BRCA-deficient tumours were also enriched for alterations within multiple genes including in the AR and PI3K pathways. Zygosity of BRCA2 alterations had no discernible impact on clinical outcomes, with similarly poor PFS for monoallelic vs biallelic loss (median 3.9 months vs 3.4 months vs copy neutral 9.8 months). These data emphasise that the BRCA genes, in particular BRCA2, are key prognostic biomarkers in mCRPC. The clinical utility of BRCA2 as a marker of poor outcomes may, at least in cfDNA assays, be independent of the zygosity state detected. Enrichment of actionable genomic alterations in cfDNA from BRCA-deficient mCRPC may support rational co-targeting strategies in future clinical trials. Several funding sources have supported this study. A full list is provided in the Acknowledgments. No funding was received from . during the conduct of the study.
登录
查看更多内容
组成型活性雄激素受体剪接变体AR-V3，AR-V7和AR-V9在castration抗性的前列腺癌转移中共表达。
影响因子：
8.8
作者：
Kallio HML;Hieta R;Latonen L;Brofeldt A;Annala M;Kivinummi K;Tammela TL;Nykter M;Isaacs WB;Lilja HG;Bova GS;Visakorpi T
通讯作者：
Visakorpi T
影响因子：
11.5
作者：
Chakraborty, Goutam;Armenia, Joshua;Kantoff, Philip W.
通讯作者：
Kantoff, Philip W.
影响因子：
64.8
作者：
Jonsson, Philip;Bandlamudi, Chaitanya;Taylor, Barry S.
通讯作者：
Taylor, Barry S.
具有转移性cast割前列腺癌的男性的鲁卡巴里（Rucaparib）具有BRCA1或BRCA2基因改变。
DOI：
10.1200/jco.20.01035
发表时间：
2020-11-10
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
Abida W;Patnaik A;Campbell D;Shapiro J;Bryce AH;McDermott R;Sautois B;Vogelzang NJ;Bambury RM;Voog E;Zhang J;Piulats JM;Ryan CJ;Merseburger AS;Daugaard G;Heidenreich A;Fizazi K;Higano CS;Krieger LE;Sternberg CN;Watkins SP;Despain D;Simmons AD;Loehr A;Dowson M;Golsorkhi T;Chowdhury S;TRITON2 investigators
通讯作者：
TRITON2 investigators
DOI：
10.1056/evidoa2200043
发表时间：
2022-09-01
期刊：
NEJM evidence
影响因子：
--
作者：
Clarke, Noel W;Armstrong, Andrew J;Saad, Fred
通讯作者：
Saad, Fred